Antimicrobial pharmacodynamics: defining regimens of antibiotics that are safe, effective and prevent the emergence of resistance

The substantial value of modern antibacterial agents is eroded by the inexorable development of antimicrobial resistance (AMR). The discovery and development of antibiotics are central aspects of addressing AMR. Since new drug-resistant mechanisms are continually arising, ways to streamline and accelerate the development of new agents are required. An understanding of dose-exposure-response (D-E-R) relationships (also pharmacokinetic-pharmacodynamic (PK-PD)) provides a means to establish causality, i.e. demonstrating that the new antibiotic acts in a predictable way and ensuring that understanding can be harnessed for therapeutic benefit. D-E-R potentially enables the adequacy of proposed regimens for effectiveness trials to be justified, minimization or replacement of dose-finding studies, selection of regimens in special populations and selection of regimens that minimize the emergence of resistance. Here, we consider the advantages of combining empirical approaches characteristic of modern PK-PD with a mechanistic understanding of drug effect and the emergence of resistance. Conceiving the approach to new dose/schedule selection in this way provides the best chance of designing regimens that are safe and effective, and that result in resistance counterselection. In terms of the latter, regimen intensification, appropriate sequencing of antibiotics and antimicrobial combinations are relevant. This article is part of the Theo Murphy meeting issue 'Evaluating anti-infective drugs'.